Prescribing information For Healthcare Professionals Only

ACTIVE INGREDIENT(S): Darunavir (as ethanolate).

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

INDICATION(S):

PREZISTA, co-administered with low dose ritonavir in combination with other antiretroviral medicinal products for treatment of patients with human immunodeficiency virus (HIV-1) infection.

PREZISTA Oral suspension, 400 mg and 800 mg tablets co-administered with cobicistat, in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adults and adolescents ≥12 years of age, weighing at least 40 kg for once daily regimens. Cobicistat is not indicated in children.

PREZISTA Oral suspension, 75 mg, 150 mg and 600 mg tablets may be used to provide suitable dose regimens:

• For the treatment of HIV-1 infection in antiretroviral treatment (ART) experienced adult patients (including highly pre-treated).
• For the treatment of HIV-1 infection in paediatric patients from age of 3 years and at least 15 kg body weight.

PREZISTA Oral suspension, 400 mg and 800 mg tablets may be used to provide suitable dose regimens in adult and paediatric patients from age 3 and at least 40kg body weight who are:

• antiretroviral therapy (ART) naïve.
• ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA <100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/l.

Genotypic or phenotypic testing (when available) and treatment history should guide use of PREZISTA.

DOSAGE & ADMINISTRATION:

Therapy should be initiated by health care provider experienced in management of HIV. Must be taken with food. PREZISTA oral suspension for patients unable to swallow tablets. If patient vomits < 4 hour after taking tablet, take another dose of PREZISTA with cobicistat or ritonavir with food as soon as possible; if > 4 hour, take next dose at regularly scheduled time.

Adults: 
ART-naïve adults: PREZISTA 800 mg once daily with cobicistat 150 mg or ritonavir 100 mg, once daily.
ART-experienced adults with no DRV-RAMs; PREZISTA 800 mg once daily with cobicistat 150 mg or ritonavir 100 mg, once daily.
All other ART-experienced adults: 600 mg PREZISTA with 100 mg ritonavir twice daily.

Children: 
ART-naïve children (3-17 years of age): 
Body weight (kg): ≥15kg to <30kg: 600 mg (6ml) PREZISTA/100 mg (1.2ml) ritonavir, once daily.
Body weight ≥30kg to <40kg: 675 mg (6.8ml) PREZISTA/100 mg (1.2ml) ritonavir, once daily.
Body weight ≥40kg: 800 mg (8ml) PREZISTA/100 mg (1.2ml) ritonavir or 150 mg (tablet) cobicistat (in adolescents ≥12 years of age), once daily.
ART-experienced children (3-17 years of age, weighing at least 15kg) with no DRV-RAMs: a regimen of PREZISTA, twice daily with ritonavir is usually recommended and in adolescents (≥12 years of age weighing at least 40 kg) PREZISTA 800/150 mg 150 mg (tablet) cobicistat once daily taken with food. Children (3-17 years of age, weighing less than 40kg): the 400 and 800 mg tablets are not suitable for this patient population. Please refer to SmPC for dosage regimens. Children (3-11 years of age weighing < 40 kg: PREZISTA taken with cobicistat no data available; not recommended.

Children:
<3 years or <15 kg body weight: Not recommended.

Elderly: Caution; limited information.
Renal impairment: No dose adjustment required for PREZISTA/ritonavir patients. No experience with PREZISTA/cobicistat. Cobicistat should not be initiated in patients with creatinine clearance less than 70ml/min if any co-administered agent requires dose adjustment based on creatinine clearance. Refer to the cobicistat SmPC.
Hepatic impairment: Caution with mild/moderate hepatic impairment; contraindicated with severe hepatic impairment.
Pregnancy and postpartum: PREZISTA/ritonavir no dose adjustment required. PREZISTA/cobicistat should not be initiated during pregnancy, women who become pregnant during therapy with PREZISTA/cobicistat should be switched to an alternative regimen.

CONTRAINDICATIONS:

Hypersensitivity to active substance or any excipients. Severe hepatic impairment. Applicable to PREZISTA/ritonavir or cobicistat: Co-administration with rifampicin or lopinavir/ritonavir combination product. Preparations containing St John's Wort. Active substances highly dependent on CYP3A for clearance including alfuzosin, amiodarone, bepridil, dronedarone, quinidine, ranolazine, ivabradine, astemizole, terfenadine, colchicine (in patients with renal and/or hepatic impairment), dihydroergotamine, ergometrine, ergotamine, methylergonovine, dapoxetine, domperidone, naloxegol, elbasvir/grazoprevir, cisapride, lurasidone, pimozide, quetiapine, sertindole, triazolam, midazolam (oral), sildenafil (for pulmonary arterial hypertension), avanafil, simvastatin, lovastatin, lomitapide, ticagrelor.

Applicable to PREZISTA/cobicistat: Active substances highly dependent on CYP3A for clearance including carbamazepine, phenobarbital and phenytoin.

SPECIAL WARNINGS & PRECAUTIONS:

Regular assessment of virological response advised. Perform resistance testing if lack/loss of virological response. Do not use PREZISTA/ritonavir or cobicistat once daily dose regimen in ART-experienced patients with one or more DRV-RAMs. Advise patients to take precautions to avoid transmission. PREZISTA must always be given with cobicistat or ritonavir, consult the cobicistat or ritonavir SmPC prior to initiation.
Severe skin reactions: Discontinue PREZISTA/ritonavir or cobicistat immediately if signs or symptoms of severe skin reactions develop. Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalised exanthematous pustulosis reported.
Rash: In clinical studies rash occurred more commonly in treatment-experienced patients receiving both PREZISTA/ritonavir + raltegravir compared to patients on PREZISTA/ritonavir without raltegravir.

Patients with known sulphonamide allergy: Caution; contains sulphonamide moiety.
Hepatotoxicity: Appropriate laboratory testing prior to initiation, with continuous monitoring during treatment. Drug-induced hepatitis reported. Patients with pre-existing liver dysfunction including chronic active hepatitis B or C have increased risk of liver function abnormalities including severe/potentially fatal hepatic adverse events should be monitored. Prompt interruption/discontinuation of treatment if liver disease develops or worsens.

Haemophiliac patients: Possibility of increased bleeding.
Pregnancy: Caution in pregnant women with concomitant medications which may further decrease darunavir exposure. Darunavir and cobicistat levels decreased when co-administered during pregnancy. May result in virological failure and increased risk of mother to child HIV transmission (see 'Pregnancy' below).
Immune reconstitution inflammatory syndrome (IRIS): Inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise in immune reactive patients with severe immune deficiency at start of combination antiretroviral therapy (CART). Autoimmune disorders reported in IRIS.
Other: Increased weight, levels of blood lipids and glucose may occur, may partly be linked to disease control and life style. Monitor blood lipids and glucose; refer to HIV treatment guidelines; manage as appropriate. Patients with advanced HIV disease and/or long-term exposure to CART may develop osteonecrosis. Life-threatening/fatal drug interactions reported in patients treated with colchicine and powerful CYP3A and P-glycoprotein inhibitors. Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir or cobicistat. If switching from ritonavir to cobicistat, caution required during first two weeks of treatment, particularly if there was a dose titration/adjustment of concomitant medication. Oral suspension contains sodium methyl parahydroxybenzoate (E219).

SIDE EFFECTS:

Refer to SmPC for other side effects.
Safety profile in children/adolescents similar to adults.

Applicable to PREZISTA/ritonavir: 
Very common: diarrhoea.
Common: hypertriglyceridaemia, diabetes mellitus, hypercholesterolaemia, hyperlipidaemia, insomnia, headache, peripheral neuropathy, dizziness, vomiting, nausea, abdominal pain, increased blood amylase, dyspepsia, abdominal distension, flatulence, increased alanine aminotransferase, rash, pruritus, asthenia, fatigue.
Other side effects: herpes simplex, thrombocytopenia, neutropenia, leukopenia, immune reconstitution inflammatory syndrome (IRIS), convulsion, (acute) myocardial infarction, angina pectoris, prolonged electrocardiogram QT, pancreatitis, haematemesis, hepatitis*, cytolytic hepatitis*, angioedema, osteonecrosis*, acute renal failure, nephrolithiasis, pyrexia, DRESS*, SJS*, erythema multiforme, TEN*, acute generalised exanthematous pustulosis*.

Applicable to PREZISTA/cobicistat: 
Very common: headache, diarrhoea, nausea, rash.
Common: (drug) hypersensitivity, anorexia, diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia, hyperlipidaemia, abnormal dreams, vomiting, abdominal pain, abdominal distension, dyspepsia, flatulence, pancreatic enzymes increased, hepatic enzyme increased, angioedema, pruritus, urticaria, myalgia, fatigue, increased blood creatinine.
Other side effects: pancreatitis acute, IRIS, crystal nephropathy.

* adverse drug reactions noted with PREZISTA®/ritonavir treatment could be expected with PREZISTA/cobicistat.

Refer to SmPC for other side effects.

PREGNANCY:

PREZISTA/ritonavir, use during pregnancy only if potential benefit justifies potential risk. PREZISTA/cobicistat should not be initiated during pregnancy. if PREZISTA/cobicistat therapy started before pregnancy, switch to an alternative regimen. PREZISTA given with low dose ritonavir may be considered as an alternative.

LACTATION:

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breastfeed.

INTERACTIONS:

Refer to the SmPC for full details before initiating therapy.
Interaction studies in adults only.

Applicable to PREZISTA/ritonavir:
Do not use: phenobarbital, phenytoin.
Not recommended: saquinavir. 
Clinical monitoring recommended &/or dose adjustment: efavirenz (should use with PREZISTA/ritonavir 600/100 mg twice daily regimen), carbamazepine, rifabutin, bosentan, indinavir.

Applicable to PREZISTA/ritonavir or cobicistat:
Do not use: voriconazole (unless positive benefit risk ratio).
Not recommended: apixaban, rivaroxaban, rifapentine, everolimus, betamethasone, mometasone, prednisone, irinotecan, triamcinolone, fluticasone, budesonide, glecaprevir/pibrentasvir, salmeterol, tadalafil (for pulmonary arterial hypertension), clopidrogel.
Use with caution: clarithromycin, artemether/lumefantrine, dasatinib, nilotinib, vinblastine, vincristine, dexamethasone (systemic), sildenafil, tadalafil, vardenafil (erectile dysfunction).
Therapeutic drug monitoring advised: disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone, ciclosporin, sirolimus, tacrolimus.
Clinical monitoring recommended &/or dose adjustment: dabigatran, edoxaban, tenofovir disoproxil, alfentanil, digoxin, warfarin (INR), clonazepam, paroxetine, sertraline, amitriptyline, desipramine, imipramine, nortriptyline, trazodone, isavuconazole, fesoterodine, solifenacin, itraconazole, fluconazole, posaconazole, clotrimazole, colchicine (normal renal / hepatic function), perphenazine, risperidone, thioridazine, carvedilol, metoprolol, timolol, amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil, prednisone, atorvastatin, pravastatin, rosuvastatin,  methadone, buprenorphine/naloxone, buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam (parenteral), zoldipem, fentanyl, oxycodone, tramadol, hormone replacement therapy (with oestrogen), drospirenone-containing product (potential hyperkalaemia).
Recommended dose: emtricitabine/tenofovir alafenamide (200/10 mg daily), maraviroc (150 mg twice daily).
No dosing recommendations: oral contraceptives alternative or additional contraceptive measures required.

Applicable to PREZISTA/cobicistat: 
Do not use: atazanavir, indinavir, saquinavir.
Not recommended: efavirenz, etravirine, nevirapine, rifabutin, bosentan.
Clinical monitoring recommended &/or dose adjustment: metformin.

Refer to SmPC for full details of interactions.

LEGAL CATEGORY: POM.

MARKETING AUTHORISATION HOLDER: 
Great Britain: Janssen-Cilag Ltd, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK.
Northern Ireland: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.

FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK.

Prescribing information last revised: December 2023